Targeting of FSP1 regulates iron homeostasis in drug-tolerant persister head and neck cancer cells via lipid-metabolism-driven ferroptosis.

BACKGROUND: Research has demonstrated that some tumor cells can transform into drug-tolerant persisters (DTPs), which serve as a reservoir for the recurrence of the disease. The persister state in cancer cells arises due to temporary molecular reprogramming, and exploring the genetic composition and microenvironment during the development of head and neck squamous cell carcinoma (HNSCC) can enhance our comprehension of the types of cell death that HNSCC, thus identifying potential targets for innovative therapies. This project investigated lipid-metabolism-driven ferroptosis and its role in drug resistance and DTP generation in HNSCC. METHODS: High levels of FSP1 were discovered in the tissues of patients who experienced relapse after cisplatin treatment. RNA sequencing indicated that a series of genes related to lipid metabolism were also highly expressed in tissues from these patients. Consistent results were obtained in primary DTP cells isolated from patients who experienced relapse. The Cancer Genome Atlas database confirmed this finding. This revealed that the activation of drug resistance in cancer cells is influenced by FSP1, intracellular iron homeostasis, and lipid metabolism. The regulatory roles of ferroptosis suppressor protein 1 (FSP1) in HNSCC metabolic regulation were investigated. RESULTS: We generated human oral squamous cell carcinoma DTP cells (HNSCC cell line) to cisplatin and observed higher expression of FSP1 and lipid-metabolism-related targets in vitro. The shFSP1 blockade attenuated HNSCC-DTP cell stemness and downregulated tumor invasion and the metastatic rate. We found that cisplatin induced FSP1/ACSL4 axis expression in HNSC-DTPC cells. Finally, we evaluated the HNSCC CSC-inhibitory functions of iFSP1 (a metabolic drug and ferroptosis inducer) used for neo-adjuvant chemotherapy; this was achieved by inducing ferroptosis in a patient-derived xenograft mouse model. CONCLUSIONS: The present findings elucidate the link between iron homeostasis, ferroptosis, and cancer metabolism in HNSCC-DTP generation and acquisition of chemoresistance. The findings may serve as a suitable model for cancer treatment testing and prediction of precision treatment outcomes. In conclusion, this study provides clinically oriented platforms for evaluating metabolism-modulating drugs (FSP1 inhibitors) and new drug candidates of drug resistance and ferroptotic biomarkers.

The Roles of Glutamate Receptors and Their Antagonists in Status Epilepticus, Refractory Status Epilepticus, and Super-Refractory Status Epilepticus.

Status epilepticus (SE) is a neurological emergency with a high mortality rate. When compared to chronic epilepsy, it is distinguished by the durability of seizures and frequent resistance to benzodiazepine (BZD). The Receptor Trafficking Hypothesis, which suggests that the downregulation of γ-Aminobutyric acid type A (GABAA) receptors, and upregulation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play major roles in the establishment of SE is the most widely accepted hypothesis underlying BZD resistance. NMDA and AMPA are ionotropic glutamate receptor families that have important excitatory roles in the central nervous system (CNS). They are both essential in maintaining the normal function of the brain and are involved in a variety of neuropsychiatric diseases, including epilepsy. Based on animal and human studies, antagonists of NMDA and AMPA receptors have a significant impact in ending SE; albeit most of them are not yet approved to be in clinically therapeutic guidelines, due to their psychomimetic adverse effects. Although there is still a dearth of randomized, prospective research, NMDA antagonists such as ketamine, magnesium sulfate, and the AMPA antagonist, perampanel, are regarded to be reasonable optional adjuvant therapies in controlling SE, refractory SE (RSE) or super-refractory SE (SRSE), though there are still a lack of randomized, prospective studies. This review seeks to summarize and update knowledge on the SE development hypothesis, as well as clinical trials using NMDA and AMPA antagonists in animal and human studies of SE investigations.

Vitamin B3 Provides Neuroprotection via Antioxidative Stress in a Rat Model of Anterior Ischemic Optic Neuropathy.

Supplementing with vitamin B3 has been reported to protect against retinal ganglion cell (RGC) damage events and exhibit multiple neuroprotective properties in a mouse model of optic nerve injury. In this study, a rat model of anterior ischemic optic neuropathy was used to assess the neuroprotective benefits of vitamin B3 (rAION). Vitamin B3 (500 mg/kg/day) or phosphate-buffered saline (PBS) was administered to the rAION-induced rats every day for 28 days. The vitamin B3-treated group had significantly higher first positive and second negative peak (P1-N2) amplitudes of flash visual-evoked potentials and RGC densities than the PBS-treated group (p < 0.05). A terminal deoxynucleotidyl transferase dUTP nick end labeling assay conducted on vitamin B3-treated rats revealed a significant reduction in apoptotic cells (p < 0.05). Superoxide dismutase and thiobarbituric acid reactive substance activity showed that vitamin B3 treatment decreased reactive oxygen species (p < 0.05). Therefore, vitamin B3 supplementation preserves vision in rAION-induced rats by reducing oxidative stress, neuroinflammation, and mitochondrial apoptosis.

Polymerization of the backbone of the pectic polysaccharide rhamnogalacturonan I.

Rhamnogalacturonan I (RG-I) is a major plant cell wall pectic polysaccharide defined by its repeating disaccharide backbone structure of [4)-α-D-GalA-(1,2)-α-L-Rha-(1,]. A family of RG-I:Rhamnosyltransferases (RRT) has previously been identified, but synthesis of the RG-I backbone has not been demonstrated in vitro because the identity of Rhamnogalacturonan I:Galaturonosyltransferase (RG-I:GalAT) was unknown. Here a putative glycosyltransferase, At1g28240/MUCI70, is shown to be an RG-I:GalAT. The name RGGAT1 is proposed to reflect the catalytic activity of this enzyme. When incubated together with the rhamnosyltransferase RRT4, the combined activities of RGGAT1 and RRT4 result in elongation of RG-I acceptors in vitro into a polymeric product. RGGAT1 is a member of a new GT family categorized as GT116, which does not group into existing GT-A clades and is phylogenetically distinct from the GALACTURONOSYLTRANSFERASE (GAUT) family of GalA transferases that synthesize the backbone of the pectin homogalacturonan. RGGAT1 has a predicted GT-A fold structure but employs a metal-independent catalytic mechanism that is rare among glycosyltransferases with this fold type. The identification of RGGAT1 and the 8-member Arabidopsis GT116 family provides a new avenue for studying the mechanism of RG-I synthesis and the function of RG-I in plants.

Composition and Bioactivity of a Modified Huang-Lian-Jie-Du Decoction.

Background: Epidermal growth factor receptor inhibitors (EGFRIs) and tyrosine kinase inhibitors (TKIs) are key drugs in targeted cancer therapy. However, they may cause skin toxicity. We previously prepared a modified Huang-Lian-Jie-Du (mHLJD) decoction cream using 10 herbs, which effectively alleviated EGFRI/TKI-induced skin toxicity. In the present study, we identified the reference markers of the mHLJD decoction and investigated the anti-inflammatory and antibacterial effects of the mHLJD decoction extract. Methods: We performed high-performance liquid chromatography (HPLC) to determine the composition of the mHLJD decoction. Human epidermoid A431 cells were treated with tumor necrosis factor (TNF)-α to induce inflammation; then, the effects of the mHLJD decoction extract on the cytokine expression were determined using a cytokine array and by performing real-time quantitative polymerase chain reaction (qPCR). The antibacterial effects of the extract were examined using disk diffusion and microdilution assays. Results: HPLC results revealed that the mHLJD decoction primarily consisted of geniposide, berberine chloride, baicalin, coptisine, and palmatine. TNF-α treatment increased the expression of certain cytokines, including IL-1ß, IL-8, M-CSF, and TGF-ß2; however, pretreatment with the mHLJD decoction extract reduced their expression. The qPCR results demonstrated a decreased mRNA expression of IL-8, M-CSF, and TGF-ß2. The antibacterial assay revealed that the extract exerted inhibitory effects on Staphylococcus aureus, forming an inhibition zone at the minimum inhibitory concentrations of 3.125 and 6.25 mg/mL; however, the extract exerted no effects on Escherichia coli and Pseudomonas aeruginosa. Conclusions. We developed an HPLC method to quantify the reference markers of the mHLJD decoction. The bioactivity analysis provided the potential mechanisms underlying the effects of the mHLJD decoction on EGFRI/TKI-induced skin toxicity.

2022 Taiwan lipid guidelines for primary prevention.

Elevated circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Early control of LDL-C to prevent ASCVD later in life is important. The Taiwan Society of Lipids and Atherosclerosis in association with the other seven societies developed this new lipid guideline focusing on subjects without clinically significant ASCVD. In this guideline for primary prevention, the recommended LDL-C target is based on risk stratification. A healthy lifestyle with recommendations for foods, dietary supplements and alcohol drinking are described. The pharmacological therapies for LDL-C reduction are recommended. The aim of this guideline is to decrease the risk of ASCVD through adequate control of dyslipidemia in Taiwan.

Inflammatory Burden and Immunomodulative Therapeutics of Cardiovascular Diseases.

Phenotyping cardiovascular illness and recognising heterogeneities within are pivotal in the contemporary era. Besides traditional risk factors, accumulated evidence suggested that a high inflammatory burden has emerged as a key characteristic modulating both the pathogenesis and progression of cardiovascular diseases, inclusive of atherosclerosis and myocardial infarction. To mechanistically elucidate the correlation, signalling pathways downstream to Toll-like receptors, nucleotide oligomerisation domain-like receptors, interleukins, tumour necrosis factor, and corresponding cytokines were raised as central mechanisms exerting the effect of inflammation. Other remarkable adjuvant factors include oxidative stress and secondary ferroptosis. These molecular discoveries have propelled pharmaceutical advancements. Statin was suggested to confer cardiovascular benefits not only by lowering cholesterol levels but also by attenuating inflammation. Colchicine was repurposed as an immunomodulator co-administered with coronary intervention. Novel interleukin-1ß and -6 antagonists exhibited promising cardiac benefits in the recent trials as well. Moreover, manipulation of gut microbiota and associated metabolites was addressed to antagonise inflammation-related cardiovascular pathophysiology. The gut-cardio-renal axis was therein established to explain the mutual interrelationship. As for future perspectives, artificial intelligence in conjunction with machine learning could better elucidate the sequencing of the microbiome and data mining. Comprehensively understanding the interplay between the gut microbiome and its cardiovascular impact will help identify future therapeutic targets, affording holistic care for patients with cardiovascular diseases.

Multiple Arabidopsis galacturonosyltransferases synthesize polymeric homogalacturonan by oligosaccharide acceptor-dependent or de novo synthesis.

Homogalacturonan (HG), the most abundant pectic glycan, functions as a cell wall structural and signaling molecule essential for plant growth, development and response to pathogens. HG exists as a component of pectic homoglycans, heteroglycans and glycoconjugates. HG is synthesized by members of the GALACTURONOSYLTRANSFERASE (GAUT) family. UDP-GalA-dependent homogalacturonan:galacturonosyltransferase (HG:GalAT) activity has previously been demonstrated for GAUTs 1, 4 and 11, as well as the GAUT1:GAUT7 complex. Here, we show that GAUTs 10, 13 and 14 are also HG:GalATs and that GAUTs 1, 10, 11, 13, 14 and 1:7 synthesize polymeric HG in vitro. Comparison of the in vitro HG:GalAT specific activities of the heterologously-expressed proteins demonstrates GAUTs 10 and 11 with the lowest, GAUT1 and GAUT13 with moderate, and GAUT14 and the GAUT1:GAUT7 complex with the highest HG:GalAT activity. GAUT13 and GAUT14 are also shown to de novo synthesize (initiate) HG synthesis in the absence of exogenous HG acceptors, an activity previously demonstrated for GAUT1:GAUT7. The rate of de novo HG synthesis by GAUT13 and GAUT14 is similar to their acceptor dependent HG synthesis, in contrast to GAUT1:GAUT7 for which de novo synthesis occurred at much lower rates than acceptor-dependent synthesis. The results suggest a unique role for de novo HG synthesis by GAUTs 13 and 14. The reducing end of GAUT13-de novo-synthesized HG has covalently attached UDP, indicating that UDP-GalA serves as both a donor and acceptor substrate during de novo HG synthesis. The functional significance of unique GAUT HG:GalAT catalytic properties in the synthesis of different pectin glycan or glycoconjugate structures is discussed.

Distal Acupoints Outperform Proximal Acupoints in Treating Knee Osteoarthritis: A Randomized Controlled Trial.

OBJECTIVES: To determine the difference in efficacy between distal and proximal acupoints in treating knee osteoarthritis. DESIGN: Ninety-two eligible participants were randomly assigned into three groups: distal acupoint treatment group (DG), proximal acupoint treatment group (PG), and sham acupuncture control group (SG). Primary and secondary outcomes were compared before and after the intervention. Interventions. A single acupuncture treatment was applied at Quchi (LI11), Shaohai (HT3), and Tianjing (TE10) in DG participants; Yanglingquan (GB34), Yinlingquan (SP9), and Heding (EX-LE2) in PG participants; and Zhongwan (CV12) and Liangmen (ST21) in SG participants. Main outcome measures. The visual analog scale (VAS) and active and passive knee range of motion (ROM) were used primarily to evaluate the treatment efficacy. The radial pulse diagnosis was used as a secondary outcome measure to determine the changes in the spectral energy of the radial pulses. RESULTS: The three groups had significant pain reduction after acupuncture (p < 0.05). DG had the greatest difference in pre- and post-VAS scores. Compared with the control group, significant improvement was observed in DG active and passive ROM and in PG passive ROM (p < 0.05). The high-frequency spectral energy of the left chi pulse in PG was significantly decreased, while the low-frequency spectral energy of the left cun pulse in PG and the left guan pulse in DG were significantly increased after acupuncture. CONCLUSIONS: Distal acupoints provide better pain relief and improve ROM than proximal acupoints in treating knee osteoarthritis. Significant changes in spectral energy were observed in the left cun, guan, and chi pulses, indicating pain relief and blood flow improvement after acupuncture.

14-Deoxy-11,12-Didehydroandrographolide Ameliorates Glucose Intolerance Enhancing the LKB1/AMPK[Formula: see text]/TBC1D1/GLUT4 Signaling Pathway and Inducing GLUT4 Expression in Myotubes and Skeletal Muscle of Obese Mice.

14-Deoxy-11,12-didehydroandrographolide (deAND), a bioactive component of Andrographis paniculata, has antidiabetic activity. AMP-activated protein kinase (AMPK) regulates glucose transport and ameliorates insulin resistance. The aim of the present study was to investigate whether activation of AMPK is involved in the mechanism by which deAND ameliorates insulin resistance in muscles. deAND amounts up to 40 [Formula: see text]M dose-dependently activated phosphorylation of AMPK[Formula: see text] and TBC1D1 in C2C12 myotubes. In addition, deAND significantly activated phosphorylation of LKB1 at 6 h after treatment, and this activation was maintained up to 48 h. deAND increased glucose uptake at 18 h after treatment, and this increase was time dependent up to 72 h. Compound C, an inhibitor of AMPK, suppressed deAND-induced phosphorylation of AMPK[Formula: see text] and TBC1D1 and reversed the effect on glucose uptake. In addition, the expression of GLUT4 mRNA and protein in C2C12 myotubes was up-regulated by deAND in a time-dependent manner. Promotion of GLUT4 gene transcription was verified by a pGL3-GLUT4 (837 bp) reporter assay. deAND also increased the nuclear translocation of MEF-2A and PPAR[Formula: see text]. After 16 weeks of feeding, the high-fat diet (HFD) inhibited phosphorylation of AMPK[Formula: see text] and TBC1D1 in skeletal muscle of obese C57BL/6JNarl mice, and deactivation of AMPK[Formula: see text] and TBC1D1 by the HFD was abolished by deAND supplementation. Supplementation with deAND significantly promoted membrane translocation of GLUT4 compared with the HFD group. Supplementation also significantly increased GLUT4 mRNA and protein expression in skeletal muscle compared with the HFD group. The hypoglycemic effects of deAND are likely associated with activation of the LKB1/AMPK[Formula: see text]/TBC1D1/GLUT4 signaling pathway and stimulation of MEF-2A- and PPAR[Formula: see text]-dependent GLUT4 gene expression, which account for the glucose uptake into skeletal muscle and lower blood glucose levels.

Oridonin Attenuates the Effects of Chronic Alcohol Consumption Inducing Oxidative, Glycative and Inflammatory Injury in the Mouse Liver.

BACKGROUND/AIM: Oridonin (Ori) is a diterpenoid naturally present in medicinal plants with a potential as an antioxidant agent. This study aimed to evaluate the hepatic anti-oxidative, anti-glycative and anti-inflammatory properties of Ori at 0.125 and 0.25% against chronic ethanol intake in mice. MATERIALS AND METHODS: Mice were divided into five groups: i) normal diet group, ii) Ori group, iii) ethanol diet (Lieber-DeCarli liquid diet with ethanol) group, iv) ethanol diet plus 0.125% Ori and v) ethanol diet plus 0.25% Ori. After 8 weeks of Ori supplementation, blood and liver tissue were used for analyses. RESULTS: Ethanol increased the production of reactive oxygen species and nitric oxide, decreased glutathione content, and lowered the activity of glutathione peroxide, glutathione reductase and catalase. Ethanol suppressed the hepatic mRNA expression of nuclear factor E2-related factor 2. Ori supplements reversed these changes. Ethanol increased hepatic Ne-(carboxyethymethyl)-lysine (CML) and pentosidine levels, and enhanced aldose reductase (AR) activity and mRNA expression. Ori supplements at only 0.25% decreased CML and pentosidine levels, and lowered the AR activity as well as its mRNA expression. Ethanol increased the hepatic release of tumor necrosis factor-alpha, transforming growth factor-beta1, interleukin (IL)-1beta and IL-6. Histological data showed that ethanol induced necrosis and inflammatory cell infiltration, while Ori supplements alleviated these inflammatory responses. Ethanol up-regulated the hepatic mRNA expression of nuclear factor kappa B, myeloperoxidase and p38. Ori supplements reversed these changes. CONCLUSIONS: These novel findings suggest that Ori could be used as a potent agent against alcohol-induced hepatotoxicity.

Effectiveness of mindfulness-based interventions on quality of life and menopausal symptoms in menopausal women: A meta-analysis.

OBJECTIVE: Menopause is a normal physiological process experienced by women, but it is often accompanied by physical and emotional symptoms that may negatively affect quality of life. This meta-analysis aimed to evaluate the effectiveness of mindfulness-based interventions on quality of life and menopausal symptoms by examining randomized controlled trials. METHODS: A systematic search was conducted across six electronic databases to collect relevant articles published up to June 30, 2020. The articles' quality was assessed using the modified Jadad scale. We performed a meta-analysis with Review Manager 5.3, calculating 95% confidence intervals and standardized mean differences, and conducted sensitivity analyses. RESULTS: The meta-analysis of five randomized controlled trials included 475 participants. The results indicated that the mindfulness-based intervention groups showed significant improvements in total quality of life and vasomotor and physical quality of life, compared to control groups (standardized mean differences range: from -0.48 to -0.68, all ps < 0.05). After the sensitivity analyses, evidence of heterogeneity remained. Insufficient data prevented conducting a meta-analysis with the sexual subscale of MENQOL or on vasomotor symptoms of menopause. CONCLUSION: For menopausal women, mindfulness-based interventions may improve quality of life (except for psychological and sexual subscales). However, there is insufficient evidence to analyze whether such interventions can reduce vasomotor-related menopausal symptoms. Although heterogeneity should be carefully assessed, mindfulness-based interventions may be a novel approach for improving women's overall quality of life during menopause. However, further research is needed to verify these effects.

Process optimization for the synthesis of ceramsites in terms of mechanical strength and phosphate adsorption capacity.

Red mud (RM), an industrial waste of bauxite refinery, shows great potential in adsorptive phosphate immobilization but granulation of RM enables the ease for field application. Red-mud-based ceramsites with 12 compositions that blended Korean red mud, American red mud, ocher, and bentonite were synthesized through firing process (600-1000 °C). The porosity, bulk density, mechanical strength, mineralogical composition, and phosphate adsorption capacity of granulated RM were characterized and analyzed. The crystallization of plagioclases, nepheline and gehlenite was observed in the ceramsites with high alkali flux content, which enhanced both porosity and phosphate adsorption capacity. The characteristics of the ceramsites without phase transition were highly correlated with porosity. The mechanical strength of ceramsites was governed by crack population, describable by the Weibull distribution model, and thus the maximal tensile stress correlated negatively with porosity. Results showed that 32 wt % of KRREM and USREM treated at 1000 and 900 °C, respectively, yielded the best performing ceramites in terms of mechanical strength and phosphate adsorption capacity. Ultimately, the phosphate adsorption capacity, as affected by initial phosphate concentration, contact time, and temperature, of the optimized ceramsites was studied.

Gastrodin alleviates seizure severity and neuronal excitotoxicities in the rat lithium-pilocarpine model of temporal lobe epilepsy via enhancing GABAergic transmission.

ETHNOPHARMACOLOGICAL RELEVANCE: Temporal lobe epilepsy remains one of the most drug-resistant focal epilepsy, leading to enormous healthcare burden. Among traditional herb medicine, some ingredients have the potential to treat seizure and alleviate the neuronal excitoxicity. The dried rhizome of Gastrodia elata Blume has been used to treat convulsive disorder, dizziness, dementia and migraine in eastern Asia. AIM OF THE STUDY: To determine whether gastrodin, an active ingredient of Gastrodia elata Blume, can reduce lithium-pilocarpine induced seizure severity and neuronal excitotoxicity and explore the underlying mechanism. MATERIALS AND METHODS: We divided the Sprague-Dawley rats into an experimental group (gastrodin group) and a control group (Dimethyl sulfoxide, vehicle group) and performed the behavioral analysis and electroencephalography to determine the effect of gastrodin on the seizure severity induced by lithium-pilocarpine injection. Nissl-stained histopathology elucidated the degree of rat hippocampal neuronal damage as markers of acute and subacute neuronal excitotoxicity. Besides, the Western blotting of dissected hippocampus was carried out to demonstrate the protein expression involving GABAergic transmission and metabolic pathway. RESULTS: Gastrodin reduced the acute seizure severity in lithium-pilocarpine-induced seizure model. In electroencephalography recording, gastrodin exerted inhibitory action on epileptiform discharge. Compared with control group, gastrodin exhibited neuroprotective effect against seizure related hippocampal neuronal damage at acute and subacute stages. The Western blotting showed that gastrodin reversed the degradation of GABAA receptor after pilocarpine-induced seizures. CONCLUSIONS: In the experimental seizure model, gastrodin showed anti-seizure and neuroprotective abilities. Enhancing the expression of GABAA receptor plays an important role in its antiepileptic mechanism. The results offer a new insight of developing new antiepileptic drugs from traditional Chinese medicine.

Increased leptin-b expression and metalloprotease expression contributed to the pyridoxine-associated toxicity in zebrafish larvae displaying seizure-like behavior.

Epilepsy is a common neurological disorder affecting people of all ages, races and ethnic backgrounds world-wide. Vitamin B6 supplementation has been widely used as an adjuvant for treating epilepsy. However, the adverse effects, including nausea and peripheral sensory neuropathy, caused by long-term and high-dose consumption of vitamin B6 have undermined the usefulness of vitamin B6 supplementation, justifying additional experimental scrutiny of vitamin B6-associated toxicity. In the current study, we found that the presence of pyridoxine, the inactive form of B6 vitamer included in most nutrient supplements, increased the mortality of the larvae displaying chemical-induced epilepsy. The expression of leptin-b, one zebrafish ortholog of human leptin, was significantly increased in the larvae displaying seizures. Increased leptin-b expression alleviated larval seizure-like behavior when exposed to epilepsy inducer, but also increased larval mortality in the presence of pyridoxine. Meanwhile, elevated adam17 and mmp13 mRNA level were found in the larvae simultaneously exposed to epilepsy-inducer and pyridoxine. Adding TNF-α inhibitor and mmp13 inhibitor effectively improved the survival of larvae injected with leptin-b mRNA and exposed to pyridoxine subsequently. We conclude that increased leptin-b and metalloprotease expression contributed, at least partly, to the pyridoxine-associated toxicity observed in larvae displaying seizures.

An Open Pilot Study of the Effect and Tolerability of Add-On Multivitamin Therapy in Patients with Intractable Focal Epilepsy.

Observational studies have investigated the potential modulatory effect of neuronal excitability by vitamins in epilepsy. We aimed to investigate whether the addition of multivitamin therapy (B6/B9, D, E and Q) to regular antiepileptic drug therapy could ameliorate seizures in patients with refractory focal epilepsy. We conducted a prospective cohort open study to investigate the effect and tolerability of add-on multivitamin therapy (daily dose: B6 100 mg, B9 5 mg, D 1000 IU, E 400 IU and coenzyme Q10 100 mg) in patients with intractable focal epilepsy. All patients had effect and safety assessments at baseline and after one, three and six months of the supplementation. Thirty patients (11 men and 19 women) with a mean age of 42.37 ± 9.40 years were recruited and four patients discontinued. The seizure frequency significantly decreased after the six-month supplementation (9.04 ± 18.16/month and 2.06 ± 3.89/month, p = 0.045). At the final visit, 62.5% of the patients showed a ≥50% reduction in seizure frequency, and 12.5% were seizure-free. As to safety and tolerability, most patients did not experience significant adverse events, although three patients reported seizure worsening. In conclusion, this pilot study demonstrated the therapeutic potential and essentially good tolerability of add-on multivitamin therapy in patients with refractory focal epilepsy.

Andrographis paniculata Improves Insulin Resistance in High-Fat Diet-Induced Obese Mice and TNFα-Treated 3T3-L1 Adipocytes.

Pro-inflammatory cytokines interfere with blood glucose homeostasis, which leads to hyperglycemia. Andrographis paniculata (AP) has been shown to possess anti-inflammatory activity and to reduce blood glucose levels in diabetes. The two major bioactive diterpenoids in AP, andrographolide (AND) and 14-deoxy-11,12-didehydroandrographolide (deAND), have potent anti-inflammatory activity. We studied whether APE (an ethanolic extract of AP), AND, and deAND could improve a high-fat diet (HFD)-induced hyperglycemia in vivo and TNF[Formula: see text]-induced impairment of insulin signaling in vitro. Male C57BL/6JNarl mice were fed a normal diet (ND) or the HFD, and the fatty mice were treated with APE, deAND, or AND for 16 weeks. 3T3-L1 cells were used to study the underlying mechanisms by which APE, deAND, or AND attenuated TNF[Formula: see text]-induced insulin resistance. The HFD significantly induced obesity, hyperglycemia, insulin resistance, and inflammation, whereas APE and deAND significantly ameliorated HFD-induced obesity, hyperglycemia, insulin resistance, and TNF[Formula: see text] production. The HFD significantly impaired insulin signaling by decreasing the protein expression of p-IRS1 tyr632 and p-AKT ser473, as well as the membrane translocation of GLUT4 in response to insulin stimulation in epididymal adipose tissue. HFD-impaired the membrane translocation of GLUT4 was significantly reversed by deAND and APE. In addition, deAND and APE markedly reversed the detrimental effect of TNF[Formula: see text] on the insulin signaling pathway and glucose uptake in 3T3-L1 cells. Despite no significant positive effect on p-AS160, a trend for recovery by deAND and APE was observed. These results suggest that deAND and APE protect against HFD-induced insulin resistance by ameliorating inflammation-driven impairment of insulin sensitivity.

Effects of mindfulness-based stress reduction on sleep quality and mental health for insomnia patients: A meta-analysis.

OBJECTIVE: Mindfulness-based stress reduction (MBSR) is a potentially effective supplement for the treatment of insomnia; however, there is no comprehensive review of its mental health effects among insomnia patients. This study aimed to synthesize relevant quantitative evidence and evaluate MBSR application and effectiveness for insomnia patients' sleep quality and mental health. METHODS: A systematic search through eight databases from the earliest available dates until August 2019 was conducted. Randomized controlled trials assessing the effects of MBSR on sleep quality, anxiety, and depression as outcome measures among insomnia patients comprising patients aged above 18 years were included in this meta-analysis. Each study's quality was assessed using the modified Jadad quality scale. The Review Manager 5.3 software was used to calculate the standardized mean differences (SMD) with 95% confidence intervals (CIs) for the data analyses. RESULTS: In total, data for 497 patients in seven randomized controlled trials were analyzed. The results revealed that compared to the control group, the MBSR group significantly improved in sleep quality (SMD = -0.69, 95% CI: -1.12~ - 0.26, Z = 3.16, p = .002), depression (SMD = -1.83, 95% CI: -2.81-0.84, Z = 3.63, p < .001), and anxiety (SMD = -1.74, 95% CI: -2.90-0.59, Z = 2.96, p = .003). A sensitivity analysis was undertaken. After carefully reviewing included trials, we can reasonably conclude that these heterogeneities did not impair the overall effect size of MBSR in the results. CONCLUSIONS: MBSR significantly improved sleep quality and mental health. Future research is needed using standardized methods examining the long-term effects of MBSR on the mental health of individuals with insomnia.

A Diterpenoid, 14-Deoxy-11, 12-Didehydroandrographolide, in Andrographis paniculata Reduces Steatohepatitis and Liver Injury in Mice Fed a High-Fat and High-Cholesterol Diet.

14-Deoxy-11,12-didehydroandrographolide (deAND), a diterpenoid in Andrographis paniculata (Burm. f.) Nees, acts as a bioactive phytonutrient that can treat many diseases. To investigate the protective effects of deAND on reducing fatty liver disease, male mice were fed a high-fat and high-cholesterol (HFHC) diet without or with 0.05% and 0.1% deAND supplementation. Cholesterol accumulation, antioxidant, and anti-inflammatory activities in liver and liver injury were evaluated after deAND treatment. The results show that deAND treatment for seven weeks reduced plasma alanine aminotransferase activity and lowered hepatic cholesterol accumulation, tumor nuclear factor-α, and histological lesions. The 0.1% deAND treatment reduced HFHC diet-induced apoptosis by lowering the caspase 3/pro-caspase 3 ratio. After 11 weeks of deAND treatment, increased NOD-like receptor protein 3 (NLRP3), capase-1, and interleukin-1ß protein levels in liver were suppressed by deAND treatment. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression, heme oxygenase-1 protein expression, and the activities of glutathione peroxidase and glutathione reductase were increased in mice fed the HFHC diet. However, those activities of antioxidant enzymes or proteins were also upregulated by 0.1% deAND treatment. Furthermore, deAND treatment tended to lower hepatic lipid peroxides. Finally, deAND treatment reversed the depletion of hepatic glutamate level induced by the HFHC diet. These results indicate that deAND may ameliorate HFHC diet-induced steatohepatitis and liver injury by increasing antioxidant and anti-inflammatory activities.

The association between clinically diagnosed insomnia and age-related macular degeneration: a population-based cohort study.

PURPOSE: The decreased level of melatonin, the substance involved in the control of the sleep-wake cycle, has been reported among the patients with age-related macular degeneration (AMD). However, knowledge about the relationship between sleep disturbance and AMD is still limited. This longitudinal case-control study aims to investigate the risk of incident AMD among the patients with clinically diagnosed insomnia using the Taiwan National Health Insurance Research Database. METHODS: The insomnia cohort (n = 15 465) consisted of newly diagnosed insomnia cases aged ≥55 years between 2000 and 2009. Subjects without insomnia, matched for age, gender and enrolment time, were randomly sampled as the control cohort (n = 92 790). Cox proportional hazard regressions were performed to calculate the hazard ratios (HR) of incident AMD for the two cohorts after adjusting for potential confounders. RESULTS: Of the 108 255 sampled subjects, 2094 (1.9%) were diagnosed with AMD, including 214 (0.2%) with neovascular AMD, during a mean follow-up period of 5.1 ± 2.8 years. Insomnia patients were more likely to have subsequent AMD than those without insomnia (2.5% versus 1.8%, p < 0.001). Further, the incidence of exudative AMD was also higher in the insomnia cohort than the control cohort (0.3% versus 0.2%, p = 0.002). The adjusted HR was 1.33 (95% confidence interval [CI], 1.18-1.48, p < 0.001) for AMD and 1.67 (95% CI, 1.20-2.33, p = 0.002) for exudative AMD. CONCLUSIONS: Clinically diagnosed insomnia is an independent indicator for the increased risk of subsequent AMD development.